Introduction and Objective: Nucleotide-binding oligomerization domain 1 (Nod1), an immune receptor, drives fat-induced insulin resistance. Recent studies show that whole-body and hematopoietic Nod1 knockout (KO) protect against insulin resistance. However, it remains uncertain whether the effect in whole-body KO is due to Nod1 deficiency in macrophages or in extra-macrophage cell(s). Nod1 is expressed in insulin-sensitive tissues, with evidence showing fatty acids activate Nod1 in adipocytes and Nod1 activators induce insulin resistance in hepatocytes, suggesting a potential role for extra-macrophage Nod1. To investigate the tissue-specific effects of Nod1, fat infusions were conducted in muscle-specific KO mice, as skeletal muscle is a primary site for insulin regulated glucose metabolism and whole-body Nod1KO mice are protected against peripheral insulin resistance.Methods: We have generated skeletal muscle specific Nod1KO mice by crossing Nod1 floxed mice with Myf6Cre+ mice. Both wild-type (WT, i.e. Nod1f/f and Myf6Cre+) and KO mice underwent a 48-hour infusion with ethylpalmitate, which is hydrolyzed in plasma into palmitate and ethanol to elevate circulating free fatty acids (FFA) in a non-toxic manner. After the infusion, we performed a hyperinsulinemic-euglycemic clamp to evaluate insulin sensitivity. A radioactive tracer (3-H3) was also used to differentiate hepatic from peripheral insulin resistance.Results: Nod1 deficiency in skeletal muscle alleviated palmitate-induced insulin resistance observed in WT mice. Tracer analysis showed that muscle Nod1KO significantly increased insulin-stimulated glucose utilization, however had no effect on hepatic glucose production.Conclusion: Our findings suggest that skeletal muscle-specific Nod1 deletion protects against palmitate-induced insulin resistance by enhancing peripheral insulin sensitivity. This highlights the critical role of muscle Nod1 in regulating insulin action and glucose metabolism.
S. Rahman: None. K. Sun: None. J. Park: None. M.A. Garcia: None. A. Giacca: None.
Canadian Institutes of Health Research (CIHR 507485)
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